The Polyol Pathway as a Mechanism for Diabetic Retinopathy: Attractive, Elusive, and Resilient

The polyol pathway is a two-step metabolic pathway in which glucose is reduced to sorbitol, which is then converted to fructose. It is one of the most attractive candidate mechanisms to explain, at least in part, the cellular toxicity of diabetic hyperglycemia because (i) it becomes active when intracellular glucose concentrations are elevated, (ii) the two enzymes are present in human tissues and organs that are sites of diabetic complications, and (iii) the products of the pathway and the altered balance of cofactors generate the types of cellular stress that occur at the sites of diabetic complications. Inhibition (or ablation) of aldose reductase, the first and rate-limiting enzyme in the pathway, reproducibly prevents diabetic retinopathy in diabetic rodent models, but the results of a major clinical trial have been disappointing. Since then, it has become evident that truly informative indicators of polyol pathway activity and/or inhibition are elusive, but are likely to be other than sorbitol levels if meant to predict accurately tissue consequences. The spectrum of abnormalities known to occur in human diabetic retinopathy has enlarged to include glial and neuronal abnormalities, which in experimental animals are mediated by the polyol pathway. The endothelial cells of human retinal vessels have been noted to have aldose reductase. Specific polymorphisms in the promoter region of the aldose reductase gene have been found associated with susceptibility or progression of diabetic retinopathy. This new knowledge has rekindled interest in a possible role of the polyol pathway in diabetic retinopathy and in methodological investigation that may prepare new clinical trials. Only new drugs that inhibit aldose reductase with higher efficacy and safety than older drugs will make possible to learn if the resilience of the polyol pathway means that it has a role in human diabetic retinopathy that should not have gone undiscovered.

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Sorbinil, an Aldose Reductase Inhibitor, in Fighting Against Diabetic Complications

Medicinal Chemistry ◽

10.2174/1573406414666180524082445 ◽

2019 ◽

Vol 15 (1) ◽

pp. 3-7 ◽

Cited By ~ 4

Author(s):

Qi Huang ◽

Qiong Liu ◽

Dongsheng Ouyang

Keyword(s):

Aldose Reductase ◽

Diabetic Complications ◽

Polyol Pathway ◽

Review Article ◽

Global Public Health ◽

Model Studies ◽

Human Use ◽

Pathway Inhibition

Background: Aldose reductase (AR) is involved in the pathogenesis of diabetes, which is one of the major threats to global public health. Objective: In this review article, we have discussed the role of sorbinil, an AR inhibitor (ARI), in preventing diabetic complications. Results: AR contributes in diabetes by generating excess intracellular superoxide and other mediators of oxidative stress through polyol pathway. Inhibition of AR activity thus might be a potential approach for the management of diabetic complications. Experimental evidences indicated that sorbinil can decrease AR activity and inhibit polyol pathway. Both in vitro and animal model studies reported the efficacy of sorbinil in controlling the progression of diabetes. Moreover, Sorbinil has been found to be comparatively safer than other ARIs for human use. But, it is still in earlyphase testing for the treatment of diabetic complications clinically. Conclusion: Sorbinil is an effective ARI, which could play therapeutic role in treating diabetes and diabetic complications. However, advanced clinical trials are required for sorbinil so that it could be applied with the lowest efficacious dose in humans.

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Curcumin Analogues with Aldose Reductase Inhibitory Activity: Synthesis, Biological Evaluation, and Molecular Docking

Processes ◽

10.3390/pr7070417 ◽

2019 ◽

Vol 7 (7) ◽

pp. 417 ◽

Cited By ~ 1

Author(s):

Dasharath Kondhare ◽

Sushma Deshmukh ◽

Harshad Lade

Keyword(s):

Molecular Docking ◽

Aldose Reductase ◽

Diabetic Complications ◽

Curcuma Longa ◽

Polyol Pathway ◽

Biological Evaluation ◽

Curcumin Analogues ◽

Ic50 Values ◽

Rate Limiting

Curcumin, a constituent of Curcuma longa, has shown numerous biological and pharmacological activities, including antidiabetic effects. Here, a novel series of curcumin analogues were synthesized and evaluated for in vitro inhibition of aldose reductase (AR), the first and rate-limiting enzyme of the polyol pathway, which plays a key role in the onset and progression of diabetic complications. Biological activity studies showed that all the curcuminoids exhibited moderate to good AR inhibitory (ARI) activities compared with that of the quercetin standard. Importantly, compounds 8d, 8h, 9c, 9e, and 10g demonstrated promising ARI activities, with the 50% inhibitory concentration (IC50) values of 5.73, 5.95, 5.11, 5.78, and 5.10 µM, respectively. Four other compounds exhibited IC50 values in the range of 6.04–6.18 µM. Methyl and methoxy derivatives showed a remarkable ARI potential compared with that of other substitutions on the aromatic ring. Molecular docking experiments demonstrated that the most active curcuminoid (10g) was able to favorably bind in the active site of the AR enzyme. The potent ARI activities exhibited by the curcuminoids were attributed to their substitution patterns on the aromatic moiety, which may provide novel leads in the development of therapeutics for the treatment of diabetic complications.

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Development of aldose reductase inhibitors for the treatment of inflammatory disorders and cancer: current drug design strategies and future directions

Current Medicinal Chemistry ◽

10.2174/0929867327666201027152737 ◽

2020 ◽

Vol 27 ◽

Author(s):

Himangshu Sonowal ◽

Kota V Ramana

Keyword(s):

Aldose Reductase ◽

Diabetic Complications ◽

Potential Role ◽

Polyol Pathway ◽

Design Strategies ◽

Future Directions ◽

Inflammatory Disorders ◽

Reductase Inhibitors ◽

Potential Use

: Aldose Reductase (AR) is an enzyme that converts glucose to sorbitol during the polyol pathway of glucose metabolism. AR has been shown to be involved in the development of secondary diabetic complications due to its involvement in causing osmotic stress as well as oxidative stress. Various AR inhibitors have been tested for their use to treat secondary diabetic complications such as retinopathy, neuropathy, and nephropathy in clinical studies. Recent studies also suggest the potential role of AR in mediating various inflammatory complications. Therefore, the studies on the development and potential use of AR inhibitors to treat inflammatory complications and cancer besides diabetes currently are on rising. Further, genetic mutagenesis studies, computer modeling, and molecular dynamics studies have helped design novel and potent AR inhibitors. This review discussed the potential new therapeutic use of AR inhibitors in targeting inflammatory disorders and cancer besides diabetic complications. Further, we summarized recent studies on how AR inhibitors have been designed and developed for therapeutic purposes in the last few decades.

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Addressing selectivity issues of aldose reductase 2 inhibitors for the management of diabetic complications

Future Medicinal Chemistry ◽

10.4155/fmc-2020-0032 ◽

2020 ◽

Vol 12 (14) ◽

pp. 1327-1358

Author(s):

Manoj Kumar ◽

Shalki Choudhary ◽

Pankaj Kumar Singh ◽

Om Silakari

Keyword(s):

Aldose Reductase ◽

Diabetic Complications ◽

Polyol Pathway ◽

Molecular Connectivity ◽

Catalytic Domains ◽

Current Review ◽

Fda Approval ◽

Us Fda ◽

Rate Limiting ◽

Target Activity

Aldose Reductase 2 (ALR2), the rate-limiting enzyme of the polyol pathway, plays an important role in detoxification of some toxic aldehydes. Under hyperglycemia, this enzyme overactivates and causes diabetic complications (DC). Therefore, ALR2 inhibition has been established as a potential approach to manage these complications. Several ALR2 inhibitors have been reported, but none of them could reach US FDA approval. One of the main reasons is their poor selectivity over ALR1, which leads to the toxicity. The current review underlines the molecular connectivity of ALR2 with DC and comparative analysis of the catalytic domains of ALR2 and ALR1, to better understand the selectivity issues. This report also discusses the key features required for ALR2 inhibition and to limit toxicity due to off-target activity.

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Aldose Reductase and the Polyol Pathway in Schwann Cells: Old and New Problems

International Journal of Molecular Sciences ◽

10.3390/ijms22031031 ◽

2021 ◽

Vol 22 (3) ◽

pp. 1031

Author(s):

Naoko Niimi ◽

Hideji Yako ◽

Shizuka Takaku ◽

Sookja K. Chung ◽

Kazunori Sango

Keyword(s):

Schwann Cells ◽

Aldose Reductase ◽

Critical Role ◽

Polyol Pathway ◽

Glucose Flux ◽

Rate Limiting ◽

Deficient Mice ◽

Excess Glucose ◽

Shed Light ◽

Immortalized Schwann Cells

Aldose reductase (AR) is a member of the reduced nicotinamide adenosine dinucleotide phosphate (NADPH)-dependent aldo-keto reductase superfamily. It is also the rate-limiting enzyme of the polyol pathway, catalyzing the conversion of glucose to sorbitol, which is subsequently converted to fructose by sorbitol dehydrogenase. AR is highly expressed by Schwann cells in the peripheral nervous system (PNS). The excess glucose flux through AR of the polyol pathway under hyperglycemic conditions has been suggested to play a critical role in the development and progression of diabetic peripheral neuropathy (DPN). Despite the intensive basic and clinical studies over the past four decades, the significance of AR over-activation as the pathogenic mechanism of DPN remains to be elucidated. Moreover, the expected efficacy of some AR inhibitors in patients with DPN has been unsatisfactory, which prompted us to further investigate and review the understanding of the physiological and pathological roles of AR in the PNS. Particularly, the investigation of AR and the polyol pathway using immortalized Schwann cells established from normal and AR-deficient mice could shed light on the causal relationship between the metabolic abnormalities of Schwann cells and discordance of axon-Schwann cell interplay in DPN, and led to the development of better therapeutic strategies against DPN.

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Rho-Kinase Inhibitors for the Treatment of Refractory Diabetic Macular Oedema

Cells ◽

10.3390/cells10071683 ◽

2021 ◽

Vol 10 (7) ◽

pp. 1683

Author(s):

Milagros Mateos-Olivares ◽

Luis García-Onrubia ◽

Fco. Javier Valentín-Bravo ◽

Rogelio González-Sarmiento ◽

Maribel Lopez-Galvez ◽

...

Keyword(s):

Diabetic Retinopathy ◽

Macular Oedema ◽

Standard Therapy ◽

Vision Loss ◽

Therapeutic Potential ◽

Rho Kinase ◽

Diabetic Macular Oedema ◽

New Drugs ◽

Anti Vegf

Diabetic macular oedema (DMO) is one of the leading causes of vision loss associated with diabetic retinopathy (DR). New insights in managing this condition have changed the paradigm in its treatment, with intravitreal injections of antivascular endothelial growth factor (anti-VEGF) having become the standard therapy for DMO worldwide. However, there is no single standard therapy for all patients DMO refractory to anti-VEGF treatment; thus, further investigation is still needed. The key obstacles in developing suitable therapeutics for refractory DMO lie in its complex pathophysiology; therefore, there is an opportunity for further improvements in the progress and applications of new drugs. Previous studies have indicated that Rho-associated kinase (Rho-kinase/ROCK) is an essential molecule in the pathogenesis of DMO. This is why the Rho/ROCK signalling pathway has been proposed as a possible target for new treatments. The present review focuses on the recent progress on the possible role of ROCK and its therapeutic potential in DMO. A systematic literature search was performed, covering the years 1991 to 2021, using the following keywords: “rho-Associated Kinas-es”, “Diabetic Retinopathy”, “Macular Edema”, “Ripasudil”, “Fasudil” and “Netarsudil”. Better insight into the pathological role of Rho-kinase/ROCK may lead to the development of new strategies for refractory DMO treatment and prevention.

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Role of PFKFB3 and PFKFB4 in Cancer: Genetic Basis, Impact on Disease Development/Progression, and Potential as Therapeutic Targets

Cancers ◽

10.3390/cancers13040909 ◽

2021 ◽

Vol 13 (4) ◽

pp. 909

Author(s):

Krzysztof Kotowski ◽

Jakub Rosik ◽

Filip Machaj ◽

Stanisław Supplitt ◽

Daniel Wiczew ◽

...

Keyword(s):

Current Knowledge ◽

Treatment Options ◽

Protein Structures ◽

New Drugs ◽

Proliferating Cells ◽

Cancer Tissues ◽

The Impact ◽

Rate Limiting ◽

Synthesis And Degradation

Glycolysis is a crucial metabolic process in rapidly proliferating cells such as cancer cells. Phosphofructokinase-1 (PFK-1) is a key rate-limiting enzyme of glycolysis. Its efficiency is allosterically regulated by numerous substances occurring in the cytoplasm. However, the most potent regulator of PFK-1 is fructose-2,6-bisphosphate (F-2,6-BP), the level of which is strongly associated with 6-phosphofructo-2-kinase/fructose-2,6-bisphosphatase activity (PFK-2/FBPase-2, PFKFB). PFK-2/FBPase-2 is a bifunctional enzyme responsible for F-2,6-BP synthesis and degradation. Four isozymes of PFKFB (PFKFB1, PFKFB2, PFKFB3, and PFKFB4) have been identified. Alterations in the levels of all PFK-2/FBPase-2 isozymes have been reported in different diseases. However, most recent studies have focused on an increased expression of PFKFB3 and PFKFB4 in cancer tissues and their role in carcinogenesis. In this review, we summarize our current knowledge on all PFKFB genes and protein structures, and emphasize important differences between the isoenzymes, which likely affect their kinase/phosphatase activities. The main focus is on the latest reports in this field of cancer research, and in particular the impact of PFKFB3 and PFKFB4 on tumor progression, metastasis, angiogenesis, and autophagy. We also present the most recent achievements in the development of new drugs targeting these isozymes. Finally, we discuss potential combination therapies using PFKFB3 inhibitors, which may represent important future cancer treatment options.

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Electroretinogram in sucrose-fed diabetic rats treated with an aldose reductase inhibitor or an anticoagulant

AJP Endocrinology and Metabolism ◽

10.1152/ajpendo.1997.273.5.e965 ◽

1997 ◽

Vol 273 (5) ◽

pp. E965-E971 ◽

Cited By ~ 5

Author(s):

Nigishi Hotta ◽

Jiro Nakamura ◽

Fumihiko Sakakibara ◽

Yoji Hamada ◽

Tomohiro Hara ◽

...

Keyword(s):

Animal Model ◽

Diabetic Retinopathy ◽

Aldose Reductase ◽

Reductase Inhibitor ◽

Polyol Pathway ◽

Aldose Reductase Inhibitor ◽

Dependent Diabetes Mellitus ◽

Pathway Activity ◽

Oletf Rats ◽

Long Evans

To investigate the role of increased polyol pathway activity and hemodynamic deficits in the pathogenesis of diabetic retinopathy in non-insulin-dependent diabetes mellitus (NIDDM), Otsuka Long-Evans Tokushima fatty (OLETF) rats, an animal model of human NIDDM, were given water with or without 30% sucrose and some of them were fed laboratory chow containing 0.03% cilostazol, an anticoagulant, or 0.05% [5-(3-thienyl)tetrazol-1-yl] acetic acid monohydrate (TAT), an aldose reductase inhibitor, for 8 wk. Long-Evans Tokushima Otsuka (LETO) rats were used as nondiabetic controls. The peak latencies of oscillatory potentials of the electroretinogram in sucrose-fed OLETF rats were significantly prolonged compared with those in OLETF rats without sucrose feeding and LETO rats. There was a marked increase in platelet aggregability and a significant decrease in erythrocyte 2,3-diphosphoglycerate in sucrose-fed OLETF rats. Cilostazol significantly improved these parameters without changes in retinal levels of sorbitol and fructose. TAT, however, ameliorated all of these parameters. These findings confirm that the sucrose-fed OLETF rat is a useful animal model of retinopathy in human NIDDM and suggest that cilostazol improved diabetic retinopathy by modifying vascular factors, not by altering polyol pathway activity.

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